Behrouzfar Kiarash, Mutsaers Steve E, Chin Wee Loong, Patrick Kimberley, Ng Isaac Trinstern, Pixley Fiona J, Morahan Grant, Lake Richard A, Fisher Scott A
National Centre for Asbestos Related Diseases, University of Western Australia, Nedlands, WA, Australia.
School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia.
iScience. 2024 Sep 23;27(10):111011. doi: 10.1016/j.isci.2024.111011. eCollection 2024 Oct 18.
Mesothelioma is a lethal cancer. Despite promising outcomes associated with immunotherapy, durable responses remain restricted to a minority of patients, highlighting the need for improved strategies that better predict outcome. Here, we described the development of a mesothelioma-specific gene signature that accurately predicts survival. Comprehensive gene expression analysis of asbestos exposed MexTAg Collaborative Cross mouse tumors revealed distinct tumor clusters characterized by epithelial mesenchymal transition/extracellular matrix, or immune infiltrate related gene expression profiles. Weighted gene co-expression network analysis (WGCNA) identified 20 hub genes that drove differential gene expression. Human homologues of these 20 hub genes were refined through univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses to identify a six-gene mesothelioma-specific prognostic signature that accurately predicted patient survival across four independent human mesothelioma datasets. Furthermore, this six-gene signature demonstrated the potential to predict treatment response, thus advancing the management of this challenging malignancy.
间皮瘤是一种致命的癌症。尽管免疫疗法带来了有前景的治疗效果，但持久缓解仍仅限于少数患者，这凸显了改进策略以更好预测治疗结果的必要性。在此，我们描述了一种能准确预测生存的间皮瘤特异性基因特征的开发过程。对暴露于石棉的MexTAg协作杂交小鼠肿瘤进行的全面基因表达分析揭示了不同的肿瘤簇，其特征在于上皮间质转化/细胞外基质或免疫浸润相关的基因表达谱。加权基因共表达网络分析（WGCNA）确定了驱动差异基因表达的20个核心基因。通过单变量Cox回归和最小绝对收缩和选择算子（LASSO）回归分析对这20个核心基因的人类同源物进行了优化，以确定一个六基因间皮瘤特异性预后特征，该特征能准确预测四个独立的人类间皮瘤数据集中患者的生存情况。此外，这个六基因特征显示出预测治疗反应的潜力，从而推动了对这种具有挑战性的恶性肿瘤的管理。
